Oral Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Dimethyl fumarate fails to enrich regulatory T cells in sporadic ALS (#58)

Jack W Rawlings 1 2 3 , Prudence N Gatt 2 , Scott N Byrne 1 2 3 , Fiona C McKay 2 4 , Steve Vucic 5 , Nicole L Fewings 2 4
  1. Charles Perkin Centre, University of Sydney, Camperdown, NSW, Australia
  2. Centre for Immunology and Allergy Research, Westmead Institute of Medical Research, Westmead, NSW, Australia
  3. School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
  4. Westmead Clinical School, University of Sydney, Westmead, NSW, Australia
  5. Brain and Nerve Research Centre, Concord Clinical School, University of Sydney, Concord, NSW , Australia

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, for which there are limited treatment options. While not understood as an immune-mediated disease – regulatory T cells (Tregs) of sporadic ALS patients are functionally impaired, total Treg counts inversely correlate with rate of disease progression and autologous infusions of expanded Tregs slowed disease progression. Tecfidera (dimethyl fumarate) is an immunomodulatory drug used in the treatment of relapsing-remitting multiple sclerosis, that has therapeutic potential in sporadic ALS, as it improves the suppressive activities of Tregs, increases the ratio of anti-inflammatory T cells (like Tregs) to pro-inflammatory subsets and favours neuroprotection through Nrf2-activation. This drug proved clinically ineffective in a phase 2 placebo-controlled study, but it remains unclear whether this represents a failure to modulate immunity or that the DMF-affected immune state does not benefit ALS patients. In this study, we characterised the circulating T cell subsets of participants of this trial (Tecfidera [n = 24], Placebo [n = 7]) at baseline and six months post-treatment using a flow cytometric approach. The absolute counts for total, CD4+ and CD8+ T cells, as well as total lymphocytes, significantly decreased. The proportion of central memory declined in both CD4+ and CD8+ compartments, and naïve T cells increased – but only within CD4+ T cells. The pro-inflammatory Th1 (CXCR3+) and Th1/17 (CCR6+ CXCR3+) subsets significantly decreased, but surprisingly so did the proportion of Tregs (FoxP3+ CD25hi CD127lo). The phenotype of Tregs was further explored with high-dimensional clustering and revealed a CD45RA+ Treg cluster that increased in proportion and three IL-6R+ clusters that decreased. These findings may in part explain the clinical inefficacy of this drug and do not preclude the future therapeutic potential of other Treg-enriching treatments. Further investigation of DMF-affected pathways is needed, as it may reveal patterns of immune dysfunction specific to ALS.